Activities of the Open-Ended Online Forum (2014-2016)

Dear members of the Online Forum,

Please use this thread to share views, relevant guidance and sources information on “Synergistic impacts of different herbicides that are part of the technology package that accompanies certain LMOs”.

Thank you,
Manoela

Dear Colleagues:

We thank the opportunity to contribute to this forum.

I have some overall knowledge of several LMO/GMO regulatory frameworks in the world. In all of them, herbicide safety is assessed separately from GM crop risk assessment. The assessment is performed by a different governmental area, using different international standards produced by different international bodies. This does not mean that the specific regulators for each type of product are isolated, there is cross talk and exchange of information when necessary.

The concept of “package” in this case may be of commercial or other relevance, but it is not applicable to risk assessment purposes. Although the products may be used in combination, they are adequately assessed separately because they require different kind of expertise, different risk hypotheses are involved, different endpoints, competent authorities, risk management measures, etc. The safety of electrical appliances and paints are assessed separately, even though some electrical appliances are painted. The safety of novel foods and food packaging materials are assessed separately, even though they can be found combined in a single product.

So it is quite surprising to see such a specific issue being proposed for inclusion in a LMO risk assessment guideline. Without prejudice of its timeliness or relevance, indeed this may not be the appropriate place to consider such issues if guidance is really intended to be used by the appropriate  regulator in the appropriate context. I declare my background with LMO safety assessment does not enable me at all to contribute with constructing guidance on herbicide chemical environmental toxicology, or other risk assessment issues related to such products. Moreover, I fear that a debate not held among the most appropriate experts in the most adequate forum may lead to misleading guidance, and misleading guidance in risk assessment issues is a serious thing. So this is the sole and only contribution I will made to this particular thread, just in case.

Having said this, the reference to “synergistic impacts” is intriguing. Does it mean that if a LMO plant is tolerant to more than one herbicide, it is presumed that those herbicides would be applied in the field in combination simultaneously? In a few cases I am familiar with, this is not the case. Herbicide resistance was stacked as a means to enable rotation in the use of herbicides with different modes of action along time, likely across different seasons or campaigns. This is a strategy to delay and eventually mitigate the emergence of herbicide-resistant weeds.

Thanks once more to the facilitators and the Secretariat for the opportunity to contribute.

Best Regards,
Martin Lema
Argentina

POSTED ON BEHALF OF SWEE LIAN TAN
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This "package" deal bothers me because it smacks too much of making the customer of the herbicide-resistant GM-seed a captive to the seller of the herbicide.  This is because the farmer will not be able the buy the GM seed on its own, and to use a similar herbicide (which perhaps is selling at a lower price).

I also think it is a good idea to do risk assessment on both the herbicide as well as the GM crop although different expertise is often required.  This will help to avoid the "overuse" of the herbicide (as some farmers have the habit of doubling or tripling the recommended dose when a herbicide works well!), leading to the problem of herbicide residues at levels which are harmful to human and animal health.

Thank you for giving me the opportunity to air my thoughts.

Swee Lian Tan

Dear colleagues,

First, thanks to Francisca for moderating this forum, never an easy task. 

Although we have been asked not to discuss whether the specific topic is a relevant topic for further discussion, I would like to support Martin Lema [#7582] who indicates that in general the safety of herbicides is assessed under another regulatory framework than that of LMOs, and this includes the safety assessment of herbicides as applied to LMOs. There is no rationale to assess the safety of the same herbicide under two different regimes. Moreover, as was also indicated earlier, the safety assessment of herbicides, whether applied in synergy of not, requires a different expertise. Therefore the rationale to include this topic in the Roadmap, other than mentioning that the safety assessment of herbicides is generally covered by other specific Regulation, is lacking. 

The argument that an ‘overuse’ of herbicides on LM crops will be prevented by assessing the combination of the LM crop and the specific herbicide under the LMO framework does not seem valid. Potential ‘overuse’ can never be excluded, irrespective the regulation the herbicide is authorized under. 


Kind regards, Boet Glandorf
GMO Office, The Netherlands

Dear Francisca, Secretariat and members of the forum

As this is my first intervention in the forum I wish to take time here to thank Francisca for her welcoming and enthusiastic invitation to participate.

A treatment of this topic should have a dedicated space in Part I. However, it might be referred to in multiple places. I will make several suggestions of where text could be particularly relevant to this issue (and thus also provide some suggestions on “relevant elements [that] should be considered related to each topic” and then make an overall recommendation of where the concentrated treatment of the topic might be best placed.

(1) Where the LMO is specifically intended for use with another product, such as one or more herbicides, then the case at hand is a combination of agrichemicals and LMO, or a combination of herbicides being used in the intended receiving environment along with the LMO. Whether the agrichemicals are applied as a mix or in series may be relevant to the risk assessment in different ways.
The combinatorial effects of multiple herbicides, whether they be additive, synergistic or antagonistic, could serve as an example in the text Part 1 beginning at line 363 “Establishing the context and scope”.
The LMO trait in such cases is observed in combination with the herbicides and each of the herbicides interacts with the plant potentially in different ways. The synergistic effects claimed for the combination of 2,4-D and glyphosate-based herbicides, for example, may occur in target, non-target organisms and the LMO, but may not be the same effect. For instance, we found that commercial formulations of herbicides based on different active ingredients induce different antibiotic resistance responses from bacteria.
Kurenbach, B., Marjoshi, D., Amabile-Cuevas, C., Ferguson, G. C., Godsoe, W., Gibson, P. & Heinemann, J. A. Sub-lethal exposure to commercial formulations of the herbicides dicamba, 2,4-D and glyphosate cause changes in antibiotic susceptibility in Escherichia coli and Salmonella enterica serovar Typhimurium. mBIO 6, e00009-00015, doi:10.1128/mBio.00009-15 (2015).
The use of different herbicides simultaneously may yield a different spectrum of sub-lethal responses in these non-target organisms than the sum of single exposures.

How or when these kinds of effects would be relevant to the environment or human health will depend on a case-by-case evaluation based on the potential receiving environment and the intended use.

(2) Another relevant section would be “Choice of comparator” perhaps around lines 429-431 “To account for variation due to interaction with the environment, the LMO and its comparator(s) should ideally be evaluated at the same time and location, and under similar environmental and management conditions.”, lines 454-455 “In some cases, the non-modified recipient organisms or the parental organisms alone may not be sufficient to establish an adequate basis for a comparative assessment.” or lines 464-465 “In cases where appropriate comparators do not exist, an alternative to the comparative approach may be needed.” There are significant challenges for conducting a comparative risk assessment based on unlike management conditions as would arise from the intended exposure of an LMO to a herbicide cocktail and a comparator that was not exposed. Consideration could be given here as to how to compensate from uncertainties, or if it is possible to do so, in the RA as a result. This issue also arises in Step 5 (see below).

(3) This topic emphasizes the effects of combinations and that is relevant in Step 1. Thus subclauses n and s lines 610-611 “Potential adverse effects resulting from the use of an LMO, such as changes in farm management practices;” where the new pesticide regime could be seen as a change in practice and line 624 “Potential adverse effects of the incidental exposure of humans to (parts of) the LMO” especially where herbicide residues may be part of the exposure are relevant links.
In addition, lines 626-629 “Potential adverse effects of changes in agricultural practices, such as type of irrigation, number and amount of herbicide applications, methods for harvesting and waste disposal, that were induced by use of the LMO. Where use of other regulated products or practices are changed, interplay with the respective risk assessments and regulations needs to be considered” could be linked to this topic.

(4) The LMO may be a conduit for use of herbicides in a qualitatively or quantitatively different way when used as intended. The trait may also cause adverse effects through gene flow if the LMO went feral or volunteers caused losses and fewer viable options for controlling the LMO were thus available. This could be linked in Step 2 to lines 679-682 “Factors that affect presence or persistence of the LMO that may lead to its establishment in the environment, such as, in the case of LM plants, lifespan, seed dormancy, ability of LM seedlings to establish among existing wild or cultivated vegetation and to reach reproductive stage, or the ability to propagate vegetatively” and line 689 “Persistence of the transgene in the ecosystem”.

(5) Relevant potential callouts in Step 3 include the topics following lines 726-728 “Relevant knowledge and experience with the non-modified recipient or parental organisms, or current use of the organism, in the likely potential receiving environment, and their interactions with other species, including sexually compatible species” and lines 749-750 “Potential adverse effects resulting from outcrossing/interbreeding to sexually compatible species and introgression of the transgene(s)”.

(6) A potential callout in Step 4 is line 782 “Individual risks and any interaction among them, such as synergism or antagonism”

(7) A step 5 callout could be place near lines 852-854 “Management options and their feasibility in the context of the intended and expected use (e.g., isolation distances to prevent outcrossing, and the use of refuge areas to minimize the development of resistance to insecticidal proteins)” or lines 861-862 “Protection goals and assessment endpoints as identified when establishing the context and scope for a risk assessment” with particular emphasis on human health protection goals.

In addition, a benefit analysis that was based on a comparison between an LMO with a dual herbicide resistance trait and its comparator may be as challenging as a comparative risk assessment, because the trait requires the use of different management practices. This could be considered in relation to lines 866-867 “Scientific benefit analyses, carried out using similar principles of sound science as those 866 used throughout the risk assessment”.

My overall recommendation, limiting my options to Part I, is for a text box in section 5 that would allow for a comprehensive integration of the RA steps applied to the topic.

As a final comment, since others have reflected on the appropriateness of a single RA framework that includes pesticides and LMOs, I would say that there can be different regulatory models and in some those tasks may be more easily combined than in others. Moreover, as mentioned by others, it is possible for one regulator to take a lead on an assessment and seek advice or collaborate with another regulator with complementary expertise. In any case, I believe that we should be considering what would make the best RA and allow countries to develop their own operations to meet that task.

Thank you for the opportunity to comment on this topic.
Best wishes
Jack

Dear colleagues,

as this is my first contribution in the forum I on the very first place wish to thank the moderators and the Secretariat for the opportunity to contribute.

My name is Werner Schenkel. I am from the Federal Office of Consumer Protection and Food Safety (BVL). In Germany the BVL is leading federal authority with regard to the fields of plant protection products and genetic engineering. Therefore, the BVL is as well responsible for the authorization of plant protection products as of experimental releases of LMO in Germany.

In spite of the institutional proximity, in Germany the herbicide safety is assessed separately from the LMO crop safety. The rationale behind this practice which is truly common in several regulatory systems worldwide including in the EU, has already been sufficiently elucidated in the contributions of Martin (#7582) and Boet (#7585). I would like to stress that the instruments of the pesticide regulations are also capable to deal with possible changes of herbicide application which may be related to e.g. the “package concept”. Not least, the pesticide regulations are likewise to be improved with regard to possible new risks of upcoming new commercial concepts.

Therefore I would like to support the conclusive view of Maria (#7593) that there is no need, neither practical nor as regards content issues to include the assessment of herbicide safety in the existing guidance. In my view the improvement of the existing guidance on the risk assessment of LMOs including the perspective that it might be finalized and presented in the next COP-MOP, is clearly overriding the motivation to extend the guidance by topics which are addressed elsewhere.

Thank you very much.

Kind regards,
Werner

Dear Francisca, Secretariat and members of the forum

First of all thank you for the opportunity to be part of the online forum. I think a short Introduction is appropriate. I work for the German federal agency for nature conservation and am a risk assessor in the field of GMO regulation since 14 years.

I would like to thank Jack for his constructive input and reply mainly on his comment.
But please forgive me, if I also want to clarify and therefore reply to the comments 7582, 7585, 7593 and 7600. I really do not want to heat up the discussion on if the subject of “Synergistic impacts of different herbicides …” should be addressed in the guidance at all. But DIRECTIVE 2001/18/EC, ANNEX II (PRINCIPLES FOR THE ENVIRONMENTAL RISK ASSESSMENT) says clearly that “Adverse effects may occur directly or indirectly through mechanisms which may include changes in management, including, where applicable, in agricultural practices.
This in my opinion is what we need to focus on and which is not risk assessed during the authorization process of herbicides. The change in the management practice in this case in the use of herbicides which is induced by the characteristics of the LMO.
This means changes in the amount of herbicides, the time of the application and the combination of different herbicides if applied combined at the same time or on the same field at different times. As conventional agricultural practice is already a big thread to biodiversity, it needs to be assessed, if the changes in herbicide use in LMO-cultures pose an additional risk on environment and nature.

Now to the topic:
I want to support Jacks statement that there are several places where the issue of synergistic impacts of different herbicides is relevant. But I think it would be best to focus on step 1: Identification of characteristics that may have adverse effects. As Jack already mentioned line 626 gives a good start. Where it says: “Potential adverse effects of changes in agricultural practices such as…, number and amount of herbicide applications, it should be added: “..and changes in the number, the application time and the combination of herbicides…” As it is a very complex issue I would propose to make a text box that could give an explanation on what needs to be considered, concerning the comparator, the synergistic effects, the change in time, amount, number and combination of applications and also links the issue to the next steps of the risk assessment. It is very similar to what Jack proposed, but my preference is to deal with this issue within the first step.

Thank you
Birgit Winkel

Dear members of the Forum,

Thank you Francisca once again for moderating the discussions.

It is my reflection that the focus here was never to access the safety of the herbicide but rather to make the exercise of trying to include herbicide information (most related to synergistic effects) in the risk assessment of the LMO tolerant to the herbicide. Therefore, the focus continues on the LMO safety. I understand the different regulatory regimes for the LMO and agrochemicals as clarified by other colleagues. However, it seems to me that the approach proposed here is quite compatible to the different regimes we have at the national level.

I would like to support Jacks suggestion on making reference to several important elements of the potential synergistic effect of the herbicide. Also, I would like to agree with Birgit as for a dedicated space in Step 1. I would like to be more specific and suggest a box after section "Points to consider regarding characterization of the LMO".

Thank you for this opportunity again.

Bets regards

sarah

Dear colleagues,

I would like to thank you for the opportunity to contribute to this forum.

Even though the instruction is to avoid a debate on whether or not the topic should be a separate guidance, or if it is relevant as a topic to be further considered, I consider it important to intervene, especially since the improvement of the existing guidance on the risk assessment of LMOs,  with the view to be finalised and presented in the next COP-MOP, is still an outstanding issue.

In this context, I would like to support the views of Martin (#7582) and Boet (7585) on the relevance of the topic to the risk assessment of LMOs. Indeed the impact of herbicides is assessed separately from LMOs, under several regulatory systems worldwide, including in the EU. In addition, for this assessment, the  required expertise is different from that required in this forum as well as from that required from the risk assessors that will use the guidance document on risk assessment of LMOs.

Given the restricted timeframe until the next COP MOP meeting, it is my belief that the inclusion of specific topics in the existing guidance should be limited to those that are relevant and will provide an added value to the quality of the existing guidance document.

Thank you very much.

Kind regards,
Maria

I would like to thank the Secretariat, and Francisca once again.  I'd also like to thank earlier participants for sharing their views and information on this topic.

Regarding the inclusion of this topic in the Roadmap, I would strongly agree with the sentiments expressed by Martin Lema (#7582), Boet Glandorf (#7585), Maria Kammenou (#7593) and Werner Schenkel (#7600).  While I don't see any suggestion on this forum that the use of herbicides and their interactions in the environment should not be assessed, the question we have in front of us is whether or not it is useful to include this as a special topic within the Roadmap and how we might do that.  I agree with the comment made by Jack Heinemann that there may be different regulatory models, however in all cases the use of the LMO is a separate decision than the use of any herbicides and independent of decisions on dose, frequency and combinations of herbicides applied.  So, trying to couple these separate activities into a single risk assessment can be problematic.  It doesn't recognize the reality that it is possible to introduce an herbicide tolerant plant into the environment without using an herbicide on it, and that with the increasing use of LMO plants that have stacked traits farmers may see a reason to do this.  It also implies that the idea of herbicide mixtures is somehow inextricably linked to LMO plants, which is hardly the case.  Luckily, in cases Jack suggests where assessors may be responsible for assessing both LMO plants and the use of herbicides they can do so making use of separate assessments very easily.

Thanks to Franseca for taking on more work and agreeing to moderate and to the Secretariat for organizing the discussion.

I would like to support both Boet and Martin and others in their views and these mirror the observations on the assessment of synergistic impacts 0f herbicides that Canada brought forward during the testing of the Roadmap. As Andrew has pointed out, the use of mixes of herbicides is not a consideration that is unique to LMOs. The use of mixes of herbicides to enhance weed control are common in conventional agriculture, for example mesotrione and atrazine can be used for effective post emergent weed control in conventional corn production or mesotrione may be used with glyphosate in a tank mix for weed control in LMO corn production . Growers choose herbicide combinations that address economically address their management concerns. With the emergence of glyphosate tolerant weeds in some cropping systems, farmers may choose other registered tools to enhance weed control and antagonism may be more of an issue than synergism. The authorization of herbicide use on a crop considers a wide range of issues that include residual time, and synergism and/or antagonism with other pesticide products that have been registered for use on that crop. As Andrew and others has pointed out, this is outside of the scope of the environmental risk assessment of an LMO crop.

Dear colleagues,

Again, many thanks to Francisca for moderating the discussion.

As the hour is growing late for this discussion, let me just voice my support for the views already stated clearly by Martin Lema (#7582), Boet Glandorf (#7585), Maria Kammenou (#7593), Werner Schenkel(#7600), Andrew Roberts, and Phil Macdonald (#7667) that this topic is outside of the scope of the environmental risk assessment of an LMO crop under Annex III of the Cartagena Protocol. These issues are addressed under other institutions, and they apply just as well to LM plants as they do to non-LM plants.

Best regards,

David Heron
Biotechnology Regulatory Services, USDA-APHIS

Thanks for the opportunities to post in this forum.

The comments posted, are reflections around the theme in question, as a part of the “brainstorming” and gathering of views mentioned in the “Gathering of views, relevant guidance and sources of information (#7574)” .

The potential of synergism of different herbicides accompanying the LMOs would rely on the herbicides in use, as these are chemicals having distinct modes of action and target points.  Each herbicide has a so-called “selectivity”, and it is important to assess the potential for a selectivity change if more than one herbicide would be applied at the same time, or after each other.
When two or more herbicides are added onto a plant; the knowledge of a potential “joint action” is important and should be assessed. In addition, the potential “joint” chemical action of the herbicides inside the plant is important, to avoid heavy use and potential side effects because of synergism. Analysis of accumulation of herbicides inside these LMOs would be a part of understanding this, also in the context related to dose and response of the herbicides used in the LMOs in question.

Best Regards.

I support the statements by Jack Heinemann [#7588], Birgit Winkel [#7608] and Sarah Agapito-Tenfen [#7617] on this topic.

We know from studies on polypharmacy that drugs of the same class can have synergistic effects so that when these drugs are used together, they can become toxic.  Different classes of drugs can also be toxic in combination. 

LMO crops that are gene-stacked to be tolerant of more than one herbicide at once have been developed, and “tank mixes” of herbicide combinations to spray on those plants have already been developed and some of these mixes have been patented.  At least one of these patents states that two such common herbicides have a synergistic herbicide effect when used in combination.  As herbicides may have an effect not only on unwanted plants (weeds) but wanted plants and animals, including vulnerable and endangered species, it is important to include in a risk assessment any synergistic effects such herbicide combinations may have, if that combination is expected to occur because it is part of the technology package.  Because different countries have different vulnerable and endangered species, it is important for each country to undertake their own risk assessment. 

Furthermore, it is clear that particular herbicides and a particular LMO come together as a single technology package, where that package may include instructions as to which herbicide mixtures to spray and when to spray for that particular LMO. More than one herbicide application may be recommended during the growth of an LM plant and the concentration of one or more of the herbicides may be different for those subsequent applications.  While the herbicide mixture may (or may not) be assessed or regulated by a separate agency in some countries, the LMO plus herbicide package is unlikely to be assessed by that agency. 

Different countries may have particular concerns about particular species that may be impacted by one of more of the herbicides in the mixture, as well as any synergistic effects of those herbicides, and those countries should be able to assess if those species will be affected by the suggested concentrations of herbicide mixtures that are scheduled to be sprayed during what may be crucial times in the lifecycle of those species (eg breeding times). 

A suitable place to put this information would be in Part II A, Risk assessment of LM plants with stacked traits, because LM pants that are resistant to more than one herbicide are usually stacked LM plants. I would place it as a separate section under “Conducting the risk assessment”

I would also include the following information in that section:

Advice to obtain any information that is given to farmers by the company marketing the LMO and herbicide package, including any technology user agreement, to determine which herbicide mixtures are to be sprayed and the schedule of when they are to be sprayed in the growing cycle of the LMO.

Advice to obtain all the information about the nature of the herbicide mixtures that will be used.  This may include looking at technical information sheets that may be supplied when a herbicide mixture is bought and/or looking at the label placed on containers of herbicide mixtures sold to farmers for e.g. toxicity information.

As extra information on the herbicide mixtures and LMOs may be found in patent information, I would include in that section advice that additional information on the LMO and/or herbicide mixtures may be found in patents held on the LMO and/or herbicide mixtures. Such patent information may be requested from the company that wishes to release the LMO into the environment, or may be found on-line.  Information that patent-associated information is available could also be listed as part of the resources available.

I would also include advice that in order to properly assess the herbicide and LMO package, animal feeding studies and toxicology studies that are supplied to the regulator should be performed using the LMO that has been sprayed as recommended or required in the technology package.

Resources for toxicology information on the herbicides used in the LMO and herbicide package should include reference to various WHO bodes such as the International Agency for Research on Cancer (IARC).

Because multi-herbicide resistant LM plants are, by definition, more able to withstand being sprayed with herbicides, they may be more inclined to become established as weeds.  Therefore, they should also be mentioned in Part III Monitoring of living modified organisms released into the environment.

Thanks Judy, the additional points you considered are in my opinion really a helpful approach to define the difference of the management practise in LMO with multiple herbicide resistance to conventional crops.
It must be taken into account that the time and combination of herbicide application can be an important factor for the effect on biodiversity. The sensitivity of non- target plants and animals may be different depending on their developmental stage. Even if the same combination of herbicides is used in Non-LMO crops the nature and the goal of the modification is that use of the herbicides is possible during the whole growing season. That is specific for LMO and can only be regarded in a risk assessment that considers the difference in the management practise. Therefore knowledge on the practise is a precondition to assess the risk, 
Regards Birgit

Hola Fran and all,
I support for the views already stated by Martin Lema (#7582), Boet Glandorf (#7585), Maria Kammenou (#7593), Werner Schenkel(#7600), Andrew Roberts, and Phil Macdonald (#7667) that this topic is outside of the scope of the environmental risk assessment of an LMO crop under Annex III of the Cartagena Protocol and covered by other regulatory frameworks.  I also agree with Phil that synergistic impacts from the use of more than one product is not inherently related to LMPs but equally so to non-LMP.

Esmeralda Prat

POSTED ON BEHALF OF MARTIN FRAMBO TAMBINYUO
(note: this message was received before the closing of the discussion, but technical issues prevented it from being posted)

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Dear members of the Forum,

Thank you Francisca for moderating the discussions.

My humble reflection that the focus here was never to access the safety of the herbicide but rather to make the exercise of trying to include herbicide information (most related to synergistic effects) in the risk assessment of the LMO tolerant to the herbicide. Hence, the focus may continue on the LMO safety. Moreover the different regulatory regimes for the LMO and agrochemicals are or maybe clarified by other colleagues. thus, it seems to me that the approach proposed here is quite compatible to the different regimes we have at the national level.

I would like to support Yanns suggestion on making reference to several important elements of the potential synergistic effect of the herbicide. Finally, I would like to agree with Birgit as for a dedicated space in Step 1. I would like to be more specific and suggest a box after section "Points to consider regarding characterization of the LMO".

Thank you for this opportunity again.

Bets regards

FRAMBO TAMBINYUO Martin